Multiple Myeloma (MM) is the second most prevalent hematological malignancy and it remains incurable with a median survival of 3-5 years. Novel therapeutic agents including bortezomib, thalidomide and lenalidomide have led to a significant advancement in the treatment of patients with this disease. However, only 25-35% of patients respond to these agents in the relapsed setting. The bone marrow (BM) microenvironment plays a pivotal role in the resistance of MM cells to therapeutic agents. We propose a clinical trial that targets the process of trafficking of MM cells and disrupt the interaction of MM cells with their microenvironment by releasing them from their protective niches into the peripheral circulation where they are more sensitive to apoptosis by other therapeutic agents. In our preliminary data, we demonstrate that the CXCR4 inhibitor AMD3100 leads to mobilization of MM cells from the BM into the peripheral blood in vivo, and that the kinetics of this process are different between MM cells and stem cells. In addition, we show that the combination of AMD3100 and bortezomib leads to an increase in mobilization of apoptotic MM cells into the peripheral circulation and a decrease in tumor burden in vivo. We hypothesize that disruption of the interaction of MM cells with their microenvironment will change their biologic properties and induce sensitivity to apoptosis. We will test this hypothesis in 3 specific aims. Specific Aim 1: To determine the safety, induction of mobilization of MM cells, and tumor response of the combination of AMD3100 and bortezomib in patients with MM through a phase I/II clinical trial in patients with relapsed MM. Specific Aim 2: To determine the biological sequelae that occur in MM cells confined to the BM compared to those outside of the BM microenvironment. Specific Aim 3: To determine the biological sequelae which occur in the BM microenvironment in response to AMD3100 and bortezomib. These studies are innovative as they represent the first in vivo trials that modulate trafficking of MM cells in patients in order to disrupt their interaction with the BM microenvironment and render them more sensitive to apoptosis. Through this clinical trial, we will investigate the biological effects of modulating cell trafficking of MM cells and other cellular and humoral components of the BM. Understanding the pathways that regulate MM cells'trafficking are critical to rationally design future therapeutic trials that specifically target the capacity of MM cells to reside in their protective environment. PUBLIC HEALTH RELEVANCE: The bone marrow microenvironment induces resistance to multiple myeloma cells and prevents their cell killing by chemotherapies. We propose a clinical trial where we will mobilize the myeloma cells out of their protective niches in the bone marrow and make them circulate in the blood where they can be easily killed by the drug bortezomib. We will perform correlative studies along with this clinical trial to understand the mechanisms of circulation of these cells out of the bone marrow.